“Ketone bodies” represent three compounds, acetone, acetoacetate and β-hydroxybutyrate that are produced in the liver by degrading fatty and released into the blood. Among the ketone bodies, acetone is very volatile and easily excreted in the expired air. Therefore, when measuring the amount of ketone bodies in the blood, total amount of acetoacetate and β-hydroxybutyrate in the blood is measured and represented as “total ketone bodies”. Ketone bodies are used as energy source together with glucose, free fatty acids or amino acids, and are utilized in various organs other than liver, such as brain, heart, kidney and skeletal muscle. Ketone bodies are very important energy source especially for brain. In the brain, only glucose and ketone bodies can be utilized as energy sources. The physiological concentration of ketone bodies varies widely dependent on the diet, excise and the like in contrast with the concentrations of other factors that are maintained within relatively narrower ranges.
It has been known that high-fat, low-carbohydrate diet induces ketone bodies and is useful for the treatment of epilepsy. It has also been known that increasing of ketone body level in the blood by means of ketogenesis induction or administration of a ketone body can provide treating and/or preventing effect against various diseases
For example, Non Patent Literature 1 discloses that mild ketosis, i.e. a mild elevation of blood ketone body level may offer therapeutic potential in a variety of conditions and diseases. Non Patent literature 1 reports that the ketogenic diet is effective for the prevention of seizures in patients with refractory epilepsy, weight loss and as adjuncts to cancer chemotherapy; that salts of ketone bodies are useful for the treatment of the decline of the concentrations of glucose, free fatty acids and glycerol in a patient receiving fluid therapy and for the treatment of genetic disease caused by the depression of acyl-CoA dehydrogenase. Further, it also reports that mild increase of the concentration of ketone bodies is effective for the treatment or prevention of: insulin resistance typical in type II diabetic patients, genetic defects of glucose transport and PHD activity; hypoglycemia; hypoxia; cardiomyopathy; hereditary muscular atrophy; diseases or conditions caused by free radicals including Parkinson's disease, and neurodegenerative disease such as Alzheimer's disease based on results of experiments using animal models.
In view of the above discussed reports, products that control ketone body level in the body have been proposed. One example of the products is a high-fat low-carbohydrate diet, i.e. a ketogenic diet. By receiving the ketogenic diet continuously, the ketogenesis in the liver is stimulated and the concentration of ketone bodies in the blood is increased. However, due to the continuous intake of the high-fat diet, the other diseases such as hyperlipidemia may be induced. In addition, no ketogenic diet product that provides satisfied taste has been provided and therefore, continuous intake of ketogenic diet is not preferable in view of QOL of the patient.
Another approach for controlling ketone body level in the body is to increase concentration of ketone bodies such as acetoacetate and D-β-hydroxybutyric acid in the blood by administering them intravenously (infusion), orally or enterally. However, administering those compounds that are acids directly in the blood is not preferable in view of keeping the blood pH around neutral. In addition, oral administration of an acid per se is difficult and therefore, derivatives of ketone bodies including salts, esters, cyclic oligomers, polymers and metabolic precursors thereof have been proposed (Patent Literatures 1-4 and Non-patent Literature 2).
Patent Literature 1 discloses that a precursor of a ketone body, such as an oligomer, polymer and ester thereof, can enhance the blood level of ketone bodies and is useful for increasing cardiac efficiency, treating diabetics and insulin resistant states and/or reversing, retarding or preventing the effects of neurodegenerative disorders and epilepsy. According to the Patent Literature 1, the number of the repeating units of the polymer may be 2 to 100 and the polymer used in the working example is an oligomer having an average degree of polymerization of 3.75 or a sodium salt of D-β-hydroxybutyric acid. 2M solution of the each was administered to a rat in an amount of 0.1 mL/100 g body weight and the blood β-hydroxybutyric acid level was monitored over 120 minutes from the administration. As a result, the highest blood β-hydroxybutyric acid level in the rat administered with the oligomer was observed at around 60 minutes after the administration, and the time was later than that when the highest β-hydroxybutyric acid level was observed in the rat received sodium salt of D-β-hydroxybutyric acid. At two hours from the administration, the blood hydroxybutyric acid level was increased 5-12 times of the normal level and concluded that those derivatives can significantly increase the blood level of ketone body for several hours from the administration.
Patent Literature 2 discloses that linear or cyclic oligomers or esters of D-β-hydroxybutyric acid can increase the blood level of hydroxybutyric acid and are effective for the reduction of protein catabolism, appetite suppression, the increase of cardiac efficiency, the treatment of diabetes and insulin resistant states, Alzheimer's disease, fronto-temperal degeneration associated with Pick's disease, vascular dementia, senile dementia of Lewy body type, dementia of Parkinsonism with frontal atrophy, progressive supranuclear palsy and corticobasal degeneration, Down's syndrome associated Alzheimer's disease, myasthenia gravis, and muscular dystrophy. In the working example, blood hydroxybutyric acid level in a dog given a single oral bolus of the cyclic trimer at 5% of the daily caloric requirement (i.e. 10 g of the cyclic trimer) was elevated. The highest level was more than 5 times of the normal level and was observed at 90 minutes from the administration. The blood level of hydroxybutyric acid was then gradually decreased over 6 hours (Example 2). In example 3, a dog was fed with 134.5 g of a mixture of meat (111 g) and the cyclic trimer (23.5 g) four times over 9 hours. The blood hydroxybutyric acid level was increased to about 50 times of the normal level within 30 minutes from the first administration. After the third administration (at 6 hours), the blood ketone body level was still 30 times of the normal level and by the next morning, returned to the normal level. Further, in Example 7, rats were fed with experimental diets containing 25% of the calories from oligomers having average molecular weight of 200 and 1000 respectively, for 5 days. The blood hydroxybutyric acid level was 9 times of the normal level in the rats fed with the oligomer of 200 MW and 2 times of the normal level in the rat fed with the oligomer of 1000 MW. Those results suggest that when the water solubility of the oligomer is decreased, the blood ketone body level will be decreased.
As discussed above, administration of the oligomer once will elevate the blood ketone body level several times within a short term and the elevated level will be kept for several hours.
Patent Literature 3 discloses to improve cerebral function by increasing blood ketone body level by means of administeration of a β-hydroxybutyric acid derivative or dimer to decamer (2-10 mer) of β-hydroxybutyric acid. Although Patent Literature 3 suggests that dimer to decamer (2-10 mer) of β-hydroxybutyric acid and esters or salts of β-hydroxybutyric acid monomer will provide similar effect on the blood ketone body level as well as on the cerebral function, only salt and ester of hydroxybutyric acid monomer were used in the working examples.
Patent Literature 4 discloses that cyclic ester of β-hydroxybutyric acid (3-hydroxybutyric acid) can elevate the blood level of ketone bodies that are β-hydroxybutyric acid and/or acetoacetate. The elevation of blood level of ketone bodies is effective for treating a cell that is subjected to malfunction due to action of free radicals, toxic agents such as peptides and proteins and genetic defects deleterious to cell metabolism, insulin resistance or other glucose metabolism defects or defect inducing states, ischemia, head trauma, and/or for increasing cell efficiency, and accordingly, is effective for the treatment of Alzheimer's disease, Parkinson's disease, amylotrophic lateral sclerosis, epilepsy, free radical disease, heart failure, Type II diabetes, deficiency or blocage of pyruvate dehydrogenase, inability to perform glycolysis in one or more cell types and Duchenne's muscular dystrophy. In Patent Literature 4, a working example in which a cyclic trimer was used as the cyclic oligomer was disclosed. At 80 minutes and 150 minutes after oral administration of the diet containing 11 wt % of the trimer, the blood level of ketone bodies were elevated to 1.8 times and 2.4 times of the normal level, respectively.
Non-patent literature 1 teaches the possibility for treating or preventing various diseases by administering ketone bodies directly into the blood by means of intravenous drip. Non-patent literature 2 teaches the possibility for increasing the blood level of ketone bodies by administering water soluble β-hydroxybutyric acid directly into the blood by means of intravenous drip. In addition it also teaches that the same effect will be obtained by the oral administration of a water soluble oligomer.
As discussed above, in the prior art references, β-hydroxybutyric acid oligomers of low polymerization degree or β-hydroxybutyric acid derivatives such as esters thereof were administered and the elevation of the blood levels of ketone bodies were confirmed. Considering the fact that the blood levels of ketone bodies were elevated soon after the administration, the oligomer of β-hydroxybutyric acid or the like might be hydrolyzed and absorbed in the stomach or small intestine; or the oligomer or the like is absorbed and transported into the blood and hydrolyzed there. That is, the ketone bodies administered in the prior art references must be water soluble. In addition, Non-Patent Literatures 1 and 2 also confirms that the compound to increase the blood levels of ketone bodies must be water soluble.
The applicant had shown in Patent Literature 5 that when a water insoluble polymer of β-hydroxy short-medium chain fatty acid is administered orally, the polymer will be delivered to the large intestine without being degraded in the stomach or short intestine, and degraded by the large intestinal bacterial flora to give the biological effect.    Patent Literature 1: JP 2000-515510A    Patent Literature 2: JP2002-521330A    Patent Literature 3: JP H10-95730A    Patent Literature 4: JP 2002-524506    Patent Literature 5: WO2005/021013    Non-Patent Literature 1: Veech, Prostaglandins, Leukotrienes and Essential Fatty Acids 70 (2004) 309-319    Non-Patent Literature 2: Rich, Proceedings of the Nutrition Society (1990) 49, 361-373
The above documents are herein incorporated by reference.